Waldenstrom's macroglobulinemia (WM) is a relatively rare post-germinal center lymphoplasmacytic tumor that secretes large amounts of IgM. Although WM has some similarities to lymphoplasmacytic lymphoma and multiple myeloma, very little is known about the molecular pathogenesis of WM. We have initiated the following studies. First, we have obtained the only putative WM cell line (WSU-WM) and have studied it by: molecular karyotypic analyses; molecular characterization of a t(8;14) translocation that dysregulates c-myc; determination of mutations in expressed mu and c-myc; and lymphochip microarray analysis of genes expressed in this line. Unfortunately, it has been impossible to obtain a primary tumor sample to prove that this line is derived from a WM tumor, so that the results on this cell line may not relate to WM tumors. Second, we have developed the technology to purify and characterize WM tumor cells, with a major focus of using FISH to detect aneuploidy of specific chromosomes plus translocations involving IgH and IgL loci. Our results indicate that IgH switch recombination and IgH translocations are rare in WM, which together with the pleotropic lymphoplasmacytic morphology suggest that a block to IgH switching and plasma cell differentiation may contribute to the pathogenesis of this tumor. In addition, our collaborative results with R. Fonseca at the Mayo Clinic show the following: WM tumors usually are diploid or near diploid with few karyotypic abnomalities, and IgH transloctions are extremely rare. These results suggest that the molecular pathogeneis of WM is more like chronic lymphocytic leukemia (CLL) than multiple myeloma (MM). Third, we are developing strategies that may enable us to immortalize WM tumor cells. Fourth, we are collaborators in a DCEG project to identify genetic abnormalities that occur in normal and tumor cells derived from individuals who are are members of families that have two or more individuals with WM or IgM MGUS. Finally, we are also collaborators in a multi-institutional chemoprevention protocol for MGUS, including IgM MGUS that can represent a premalignant stage of WM. We will also be analyzing the MGUS samples for karyotypic abnormalities as described above when this protocol begins.